PROJECT 2 Despite unprecedented successes in many tumor types, molecular targeted therapeutics focused on targeting activated/amplified oncogenes have not had a meaningful clinical impact on patients with the incurable brain tumor glioblastoma multiforme (GBM). In this proposal we take a radically different approach to targeted therapeutics by exploiting genomic deletions, rather than mutant oncogenes, as points of selective vulnerability. Deletions create attractive therapeutic opportunities as they are usually homogenously distributed, persist during tumor recurrence, and most importantly, can expose pharmacologically targetable vulnerabilities by collaterally deleting nearby redundant metabolic housekeeping genes. We explored this concept by utilizing an unbiased chemical biology approach to identify pharmacologically targetable vulnerabilities exposed by passenger deletions. We found that inhibitors of mitochondrial oxidative phosphorylation (OxPhos) are selectively toxic to glioma cells that contained collateral homozygous deletions in the glycolytic gene ENO1. We hypothesized that the basis for this selective vulnerability is glycolysis-deficiency: ENO1-deleted glioma cells are unable to upregulate glycolysis in the face of OxPhos inhibition, a compensatory response in normal cells (Pasteur effect). A corollary of this hypothesis is that other deletions that cause glycolysis deficiency also sensitize to OxPhos inhibitors. Tool compound OxPhos inhibitors have been extensively used in in vitro studies, but are not drug-like and have poor pharmacology. MD Anderson?s Institute of Applied Cancer Science (IACS) developed a highly potent and specific OxPhos inhibitor, IACS-010759, with nM affinity for mitochondrial complex I, which readily passes the blood brain barrier and is endowed with superb pharmacological properties. In preliminary data we demonstrated that IACS-010759 destroys glycolysis-deficient glioma cells in culture and eradicates intracranial xenografts. Preliminary data indicate that the hypoxia PET probe 18F-fluoroazomycin-arabinoside (18F-FAZA) can be used as a non-invasive in vivo read-out for OxPhos inhibition (target-engagement marker for IACS- 010759), because mitochondrial oxygen consumption is a major driver of tumor-hypoxia. Based on these exceptionally encouraging pre-clinical results, we will conduct a trial of IACS-010759 on GBM patients with 18F- FAZA as a target engagement marker. The goal of this proposal is to support this trial by: 1) pre-clinically validating glycolytic-deficiency as a responder hypothesis and identifying other deletions which confer sensitivity to IACS-010759 by this mechanism, 2) validating 18F-FAZA as a non-invasive read-out for OxPhos inhibition and as a predictor of drug-response in glycolytically deficient tumors, and 3) determining target engagement (OxPhos inhibition) by 18F-FAZA and biochemical response to IACS-010759 in patients with GBMs. This proposal stands to be the first example of precision medicine for the treatment of GBMs and provides clinical validation of collateral deletions as targetable phenomena.
PROJECT 2 Precision medicine has proved a disappointment for the treatment of glioblastoma multiforme (GBM), a deadly form of brain cancer that remains all but invariably fatal. Rather than iterating past approaches targeting amplified or mutated oncogenes, Project 2 will pioneer a new approach to precision medicine, utilizing metabolic weaknesses exposed by genomic deletions as points of vulnerability. Exceptionally encouraging pre-clinical data showing eradication of intracranial xenografted tumors, underlie an upcoming trial of a novel mitochondrial complex I inhibitor, IACS-010759, for the treatment of GBM with genomic deletions in glycolysis genes, and using the PET imaging agent 18F-FAZA as a target engagement marker.
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